The endocannabinoid system (ECS) is a pan-organ lipid signaling network that modulates numerous biological processes, including neurotransmission and immune function (Maccarrone 2014). The major endogenous agonists (i.e., endocannabinoids, ECs) for cannabinoid receptors CB1 and CB2 are the arachidonic acid (AA)-derived lipids 2-arachidonoyl glycerol (2-AG) and N-arachidonoylethanolamine (anandamide, AEA). Altered endocannabinoid signaling in the brain has been implicated in nociception, learning and memory, anxiety, and depression (Piomelli 2014, Mechoulam 2013, Lutz 2015). The indirect modulation of endocannabinoid levels may lead to less side effects than the direct activation of CB1 receptors in terms of neurotransmission, metabolism and immunomodulation.
CB1 receptor agonists are intrinsically associated with strong central side effects that are far less pronounced for increasing endocannabinoid levels upon blockage of the main endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). In addition to general anti-inflammatory and analgesic effects, the modulation of endocannabinoid tissue concentrations is a promising therapeutic approach to treat diseases related to the central nervous system (CNS) (Lutz 2015). Pharmacological strategies to treat neuropsychiatric disorders currently focus on the inhibition of endocannabinoid degradation (Batista 2014). FAAH and MAGL inhibitors such as URB597 and JZL184, respectively, have been instrumental to elucidate the role of anandamide and 2-arachidonoyl glycerol in rodent models of anxiety and depression, (Nicolussi&Gertsch 2015). Although anandamide and 2-arachidonoyl glycerol have different intracellular fates, they may share a common mechanism of membrane trafficking that is selective for endocannabinoids over arachidonate and other N-acylethanolamines (NAEs) (Chicca 2012, Beltramo 1997, Hillard 1997, Fegley 2004). However, while suitable inhibitors are available for most targets within the endocannabinoid system, the existing anandamide uptake inhibitors lack potency and show poor selectivity over the other components of the endocannabinoid system, in particular FAAH (Nicolussi&Gertsch 2015).
Current uptake inhibitors are poorly bioavailable to the central nervous system (CNS) and weakly selective because they also inhibit FAAH, the major anandamide-degrading enzyme. Few studies have addressed the uptake inhibition of 2-AG, which is the major endocannabinoid. Thus, more potent and more selective inhibitors are necessary to provide pharmaceutically useful inhibitors.